Comparative assessment of antitumor effects and autophagy induction as a resistance mechanism by cytotoxics and EZH2 inhibition in INI1-negative epithelioid sarcoma patient-derived xenograft

Silvia Stacchiotti, Valentina Zuco, Monica Tortoreto, Denis Cominetti, Anna Maria Frezza, Stefano Percio, Valentina Indio, Marta Barisella, Valentina Monti, Silvia Brich, Annalisa Astolfi, Chiara Colombo, Sandro Pasquali, Marco Folini, Mrinal M. Gounder, Maria A. Pantaleo, Paola Collini, Angelo Paolo Dei Tos, Paolo Giovanni Casali, Alessandro GronchiNadia Zaffaroni

Research output: Contribution to journalArticlepeer-review

Abstract

Epithelioid sarcoma (ES) is a rare mesenchymal malignancy marked by SMARCB1/INI1 deficiency. Retrospective clinical data report on the activity of anthracycline-and gemcitabine-based regimens. EZH2 inhibitors are currently being tested in clinical trials. Since comparisons of these agents are unlikely to be prospectively evaluated in the clinics, we took advantage of an INI1-deficient proximal-type ES patient-derived xenograft (PDX ES-1) to comparatively assess its preclinical antitumor activity. Mice were treated with doxorubicin and ifosfamide, singly or in combination, gemcitabine, and the EZH2 inhibitor EPZ-011989. Comparable antitumor activity (max tumor volume inhibition: ~90%) was caused by gemcitabine, EPZ-011989, and the doxorubicin–ifosfamide combination. The integration of RNAseq data, generated on tumors obtained from untreated and EPZ-011989-treated mice, and results from functional studies, carried out on the PDX-derived ES-1 cell line, revealed autophagy induction as a possible survival mechanism in residual tumor cells following EPZ-011989 treatment and identified HMGA2 as a main player in this process. Our data support the clinical use of gemcitabine and the doxorubicin–ifosfamide combination, confirm EZH2 as a therapeutic target in proximal-type ES, and suggest autophagy as a cytoprotective mechanism against EZH2 inhibition.

Original languageEnglish
Article number1015
JournalCancers
Volume11
Issue number7
DOIs
Publication statusPublished - Jul 2019

Keywords

  • Autophagy
  • Epithelioid sarcoma
  • EZH2
  • HMGA2
  • PDX

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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